The bone marrow microenvironment supports growth and differentiation of normal hematopoietic cells and can contribute to malignant growth. Since myeloma cells localize and accumulate in bone marrow, it is important to understand the influence of the bone marrow microenvironment not only on the growth of the malignant cells, but also on the therapeutic response of myeloma cells. Growth factors such as interleukin-6 (IL-6) produced by bone marrow stromal cells can protect myeloma cells from glucocorticoid-induced apoptosis. We examined the effect of myeloma cells-bone marrow stromal cells interaction in vitro on several therapeutic treatments. An interleukin-6-dependent myeloma cell line ANBL6 was used and treated with dexamethasone, doxorubicin, and melphalan in the presence of bone marrow stromal cells. Stromal cells were able to protect ANBL6 from dexamethasone, but significantly enhanced the effect of doxorubicin and melphalan. IL-6-induced bcl-XL and cyclin D2 expression in ANBL6 cells, but dexamethasone was able to suppress both bcl-XL and cyclin D2 expression in ANBL6. Doxorubicin and melphalan were able to suppress bcl-XL expression only in the presence of IL-6. We also looked at the effect of activating mutations of N-ras in myeloma cells interacting with stromal cells on therapeutic responses. Surprisingly, ANBL6 N-ras shows significant resistance to all drugs used. Notably, the presence of stromal cells did not alter ANBL6 Nras cells' drug resistance. These results suggest both the bone marrow microenvironment and genetic alterations of myeloma cells can independently impact on therapeutic responses.